Abstract
Metastatic cascade in malignant tumors, including breast cancer, starts with localized invasion of the host tissue. This process, requiring that tumor cells separate from each other, includes loss of homotypic and heterotypic cell adhesion and cell-cell contact inhibition, acquisition of motility, exacerbated by "epithelial-to-mesenchymal transition", and production of proteolytic enzymes which degrade basal membrane and extracellular matrix. In this sense, aside from urokinase type plasminogen activator, increased expression and activity of matrix metalloproteinases (MMPs) is one of the earliest and most sustained events in tumor progression, playing a role in angiogenesis, invasion and metastasis. MMPs are a family of 23 zinc metalloproteinases, secreted as latent pro-enzymes, activated by proteolytic cleavage, and inhibited by the tissue inhibitors of metalloproteinases. The most commonly connected MMPs with the processes of metastasis are MMP-2 (gelatinase A) and MMP-9 (gelatinase B), due to their ability to degrade collagen type IV, major component of vascular basement membrane. MMP-2 and MMP-9 are also required for the switch to the "angiogenic phenotype" during tumor progression and activation of dormant tumor cells. The association of the increase in serum MMP-2 and MMP-9 activity and clinical stage suggests the usefulness of these parameters as markers in the follow-up and prognosis of breast cancer patients. The concept of "stromal-directed therapy" of cancer, with MMP-inhibitors directed against MMPs as targets, is based on the observed MMP up-regulation in tumors.
Highlights
matrix metalloproteinases (MMPs) are a family of structurally related zinc-dependent endopeptidases that are engaged, aside from various physiological processes such as embryogenesis, reproduction, uterine involution, angiogenesis, in pathological conditions, such as tumor invasion, by mediating degradation of basement membrane and remodeling of extracellular matrix
epithelial-to-mesenchymal transition (EMT) is characterized by proteolytic loss of E-cadherin or Endothelial - to Neural-cadherin (N-cadherin) “switching” and by increasing motility plays a crucial role during invasion and metastasis of carcinomas [3]
Breast cancer may be subclassified into luminal, basal, and HER2 subtypes with distinct differences in prognosis and response to therapy
Summary
MMPs are a family of structurally related zinc-dependent endopeptidases that are engaged, aside from various physiological processes such as embryogenesis, reproduction, uterine involution, angiogenesis, in pathological conditions, such as tumor invasion, by mediating degradation of basement membrane and remodeling of extracellular matrix. Constitutive expression of active stromelysin in mammary epithelial cells results in cleavage of E-cadherin and progressive phenotypic changes in vitro, including loss of catenins from cell-cell contacts, down-regulation of cytokeratins, and up-regulation of vimentin and MMP-9. These changes result in a stable epithelial to mesenchymal transition of cellular phenotype. Progression toward malignancy is accompanied by loss of epithelial differentiation and a shift towards a mesenchymal phenotype This process, referred to as epithelial-to-mesenchymal transition (EMT), exacerbates motility and invasiveness of ZZZRQNQVDF\X$UFKLYH'HFHPEHU 136 many cell types and it is considered as a crucial event in late stage tumorigenesis and a prerequisite for tumor infiltration and metastasis [6]. The anchorage-independent growth of tumor cells may result from an uncoupling of cell survival signals transduced from the ECM by attachment, coupled with activation of cell-cycle progression is associated with neoplastic transformation [12]
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